The long-term goal of this research is to treat type I, insulin-deficient diabetes mellitus by transplantation of pancreatic islets. The immediate goal of the proposed investigations is to test our hypothesis, in NIH miniature pigs, that combined transplantation of adult and immature (fetal or newborn) islets is more effective for long-term treatment of diabetes than either adult or immature islets alone. Clinically feasible islet transplants must fulfill two fundamental requirements; transplanted islets should reestablish normoglycemia soon after grafting and remain fully functional for a long period, ideally for a life-time. Neither adult nor fetal islet transplants satisfies these needs. However, grafts consisting of both types of islets would cover the shortcomings of each to fulfil the clinical requirements. Using fetal pancreata, we have already established transplantation procedures for successful allografts in this animal model. These procedures include assays for donor tissue immunogenicity, culture protocols for donor tissue immunoalteration, surgical techniques and immunosuppressive regimens for recipients. These procedures and basic knowledge together with recently developed techniques for adult pig islet isolation will allow us to perform combined islet transplantation in diabetic pigs. The specific objectives of the research program include; 1. Determination of effective donor tissue amounts in combined adult and fetal islet transplantation, monitoring and evaluation of glucose metabolism and determination of long-term reversal of diabetes.2. Demonstration of complete reversal of diabetes by cryopreserved adult and fetal islets.3. Determination of the means for achieving successful combined islet allografts in diabetic kidney recipients. These studies are a direct extension of our current investigations and directly relate to clinical transplantation.